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Frat Oncoproteins Act at the Crossroad of Canonical and Noncanonical Wnt-Signaling Pathways

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Frat Oncoproteins Act at the Crossroad of Canonical and Noncanonical Wnt-Signaling Pathways Oncogene (2010) 29, 93–104 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc ORIGINAL ARTICLE Frat oncoproteins act at the crossroad of canonical and noncanonical Wnt-signaling pathways R van Amerongen1,2,5, MC Nawijn1,2,6, J-P Lambooij1,2, N Proost1,2, J Jonkers3 and A Berns1,2,4 1Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands; 2Centre of Biomedical Genetics, Amsterdam, The Netherlands; 3Division of Molecular Biology, Amsterdam, The Netherlands and 4Academic Medical Center, Amsterdam, The Netherlands Wnt-signal transduction is critical for development and out the animal kingdom. Although Wnt proteins can tissue homeostasis in a wide range of animal species and is elicit multiple intracellular responses, activation of the frequently deregulated in human cancers. Members of the so-called ‘canonical’ or ‘Wnt/b-catenin’ pathway is Frat/GBP family of glycogen synthase kinase 3b (Gsk3b)- currently best understood. In the absence of extra- binding oncoproteins are recognized as potent activators of cellular Wnt, free cytoplasmic b-catenin is sequeste- the Wnt/b-catenin pathway in vertebrates. Here, we reveal red by a multiprotein complex containing APC, Axin1, a novel, Gsk3b-independent function of Frat converging casein kinase I, and glycogen synthase kinase 3b on the activation of JNK and AP-1. Both these have (Gsk3b). Sequential phosphorylation of b-catenin by been used as readouts for the noncanonical Frizzled/PCP the latter two kinases ensures its rapid degradation by pathway, which controls polarized cell movements and the the proteasome (Figure 1a). Binding of Wnt to the establishment of tissue polarity. We find that Frat Frizzled/LRP transmembrane receptor complex results synergizes with Diversin, the mammalian homolog of the in inhibition of Axin and Gsk3b, allowing the accumu- Drosophila PCP protein diego, in the activation of JNK/ lation of transcriptionally active b-catenin/TCF com- AP-1 signaling. Importantly, Frat mutants deficient for plexes (Figure 1b). The initiation of Wnt/b-catenin binding to Gsk3b retain oncogenic activity in vivo, signaling remains an area of intense study, and although suggesting that Wnt/b-catenin-independent events contri- some of the initiating events at the cell membrane have bute to Frat-induced malignant transformation. The been revealed (Bilic et al., 2007; Zeng et al., 2008), the observed activities of Frat are reminiscent of the dual precise mechanism behind Gsk3b inhibition remains to function of Dishevelled in the Wnt/b-catenin and Frizzled/ be resolved. PCP pathways and suggest that Frat may also function to In vertebrates, members of the Frat/GBP family of bridge canonical and noncanonical Wnt pathways. Gsk3b-binding proteins have been shown to compete Oncogene (2010) 29, 93–104; doi:10.1038/onc.2009.310; with Axin for binding to Gsk3b (Yost et al., 1998; Li published online 5 October 2009 et al., 1999a; Ferkey and Kimelman, 2002; Fraser et al., 2002), thereby disrupting the destruction complex and Keywords: Frat; Gsk3-binding protein; lymphoma- causing the accumulation of b-catenin (Figure 1c). genesis; Diversin; Wnt-signal transduction; planar cell Whereas the amphibian Frat ortholog GBP is critically polarity required for axis formation in Xenopus as part of the maternal Wnt pathway (Yost et al., 1998), Frat triple- knockout mice are viable without any overt phenotypic aberrations, indicating that Frat is not essential for Introduction Wnt/b-catenin signaling in mammals (van Amerongen et al., 2005). However, in support of a function for Frat Wnt-signaling controls a variety of biological processes, in canonical Wnt-signal transduction, the endogenous including cell proliferation, cell-fate decisions, and Frat-expression pattern shows remarkable overlap with polarized cell movements. As such, it is crucial for known anatomical sites of active Wnt/b-catenin signal- development and tissue homeostasis in species through- ing (Maretto et al., 2003; van Amerongen et al., 2005). This, together with the fact that Frat remains one of the most potent activators of b-catenin/TCF signaling Correspondence: Dr A Berns, Department of Molecular Genetics, identified to date, suggests that Frat acts as a modifier Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, to amplify canonical Wnt-pathway activity only under The Netherlands. E-mail: [email protected] specific circumstances. 5Current address: Department of Developmental Biology, Stanford The founding member of the Frat/GBP family, Frat1, University, Stanford, CA 94305, USA. was originally identified as a proto-oncogene in 6Current address: Laboratory Allergology and Pulmonary Diseases, advanced murine T-cell lymphomas (Jonkers et al., Section Pathology and Medical Biology, Groningen University Medical Centre, 9713 GZ, Groningen, The Netherlands. 1997). FRAT overexpression has been observed in a Received 25 March 2009; revised 3 August 2009; accepted 30 limited number of human malignancies (Saitoh and August 2009; published online 5 October 2009 Katoh, 2001; Wang et al., 2006c). FRAT1 was recently Frat activates JNK/AP-1 independent from GSK3 R van Amerongen et al 94 Wnt Frizzled/LRP Frizzled/LRP Frizzled/LRP Frizzled Frat/GBP Dvl Dvl Axin/APC/Gsk3 Axin/APC/Gsk3 Axin/APC/Gsk3 JNK Axin/APC/Gsk3 β-catenin β-catenin β -catenin β-catenin β-catenin β-catenin β-catenin β-catenin/TCF β-catenin/TCF β -catenin AP-1 TCF TCF target genes TCF target genes target genes Wnt/β-catenin OFF Wnt/β-catenin ON Frat/GBP mediated activation Dishevelled functions at the crossroad of of the Wnt/β-catenin pathway Wnt/β-catenin and Frizzled/PCP signaling through inhibition of Gsk3b TOPFLASH luciferase reporter AP-1 luciferase reporter 40 9 8 C Δ myc 7 30 Frat1 Frat1 Frat2 Δ 6 Dvl2 Frat1Frat1 C Frat2 myc 5 20 4 3 10 2 Fold activity relative to vector 1 0 0 vector Dvl2 Frat1 Frat1ΔC Frat2 vector Dvl2 Frat1 Frat1ΔC Frat2 Figure 1 The function of Frat and Dishevelled in Wnt-pathway activation. (a) In the absence of extracellular Wnt, the levels of cytoplasmic b-catenin are controlled by a multiprotein complex containing Axin, APC, and Gsk3b. (b) Binding of Wnt proteins to the Frizzled/LRP receptor complex causes the inhibition of Axin and Gsk3b, allowing b-catenin to accumulate and interact with transcription factors of the TCF/LEF family. (c) Vertebrate Frat/GBP proteins, whereas not critically required for Wnt/b-catenin signaling, are potent inhibitors of Gsk3b and cause an increase in b-catenin/TCF-dependent transcription. (d) Dishevelled functions at the crossroad of Wnt/b-catenin and Frizzled/PCP pathways. It promotes signaling through b-catenin/TCF, but has also been shown to induce the activity of JNK and AP-1. (e) Increasing amounts (25, 50, and 100 ng of DNA transfected) of Dvl2, Frat1, and Frat2 are all able to induce Wnt/b-catenin signaling in 293T cells, as evidenced by the concentration-dependent activation of the b-catenin/TCF- responsive TOPFLASH luciferase reporter. Frat2 is the least potent in this assay. Inset is a western blot depicting the expression levels of Frat1, Frat1DC and Frat2 after detection with an antibody directed against the myc-tag. (f) Increasing amounts (50, 100, and 300 ng of DNA transfected) of Frat2 and Dvl2, but not Frat1, induce a dose-dependent response of an AP-1 luciferase reporter containing seven multimerized AP-1 consensus sites. This effect is not merely because of a difference in protein stability between Frat1 and Frat2, as Frat1DC, which accumulates to higher levels than Frat1 (van Amerongen et al., 2004), is also unable to activate AP-1-dependent transcription. Data are represented as mean±s.e. Inset is a western blot depicting the expression levels of Frat1, Frat1DC, and Frat2 after detection with an antibody directed against the myc-tag. reported to be overexpressed in esophageal squamous is also required for the establishment of tissue polarity cell carcinomas, in which its expression levels were (Figure 1d; Wallingford et al., 2000; Hamblet et al., shown to correlate with the accumulation of b-catenin 2002; Wang et al., 2006a; Etheridge et al., 2008). Here, it (Wang et al., 2008). However, we have been unable functions as a critical component of a ‘noncanonical’ to find direct evidence for increased signaling through Wnt pathway, hereafter referred to as Frizzled/PCP b-catenin/TCF in murine T-cell lymphomas with signaling, mediated through JNK and AP-1 (reviewed in an activated Frat1 allele (our unpublished results), Fanto and McNeill, 2004; Klein and Mlodzik, 2005; indicating that Frat might act on a divergent pathway Jones and Chen, 2007; Wang and Nathans, 2007). in this context. We hypothesized that Frat might also have a dual Frat/GBP has earlier also been shown to interact with function. Our data show that Frat activates JNK and Dishevelled (Yost et al., 1998; Li et al., 1999a; Fraser AP-1 in a Gsk3b-independent manner and to a similar et al., 2002). This observation has thus far been degree as Dvl. Of note, the Gsk3b-binding domain of explained by a model in which Frat bridges signaling Frat is dispensable for its oncogenic activity. We further from Dvl to Gsk3b in activation of the Wnt/b-catenin find that Frat synergizes with Diversin, the mammalian pathway. However, Dishevelled has a dual function, and homolog of the Drosophila PCP protein diego,inthe in addition to activating the Wnt/b-catenin pathway, it activation of both b-catenin/TCF and JNK/AP-1 signaling. Oncogene Frat activates JNK/AP-1 independent from GSK3 R van Amerongen et al 95 As we also observe endogenous expression of Frat2 at phospho-specific antibody directed against the JNK anatomical sites displaying Frizzled/PCP-pathway activity, target residue, Ser63. In agreement with the observed we propose that Frat proteins function at the crossroad increase in JNK kinase activity, we detected elevated of Wnt/b-catenin and Frizzled/PCP-signaling pathways.
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